The increasing prevalence of genital herpes infections has reached a level of public health concern. Secondary complications, including elevated abortion rates, increases in the incidence of fetal malformations, and severe herpetic infections of newborn infants are particularly worrisome. In view of the absence of effective means for preventing herpetic recurrences, this proposal is directed towards the development of a basic understanding of the immune response to HSV antigens seen in patients with recurrent genital disease. The working hypothesis, supported by our data and consistent with independently generated evidence, is that patients with a history of recurrent lesions suffer from an impaired conversion of memory to effector cells. It posits regulatory aspects of viral specific CMI at the center of the recurrent herpetic disease problem by predicting that the speed and efficacy of the generation of active CMI response from a state of immune memory will determine the clinical outcome of the recurrent event. It suggests that recurrent lesions result from unimpeded virus replication occurring as a consequence of an inappropriate number (or functionally impaired) fully differentiating CMI effectors. However, the mechanism of the impaired generation of anamnestic effector function that is reflected in patients with recurrent disease by altered kinetic and dose response patterns of in vitro secondary responses and its relationship, if any, to clinical symptoms remain to be determined. In accordance with these interpretations, we describe three theoretical mechanisms, each amenable to laboratory testing, whereby the onset of a recrudescent episode may fail to be met with a sufficient number (or may be met by functionally impaired) effector cells.